EP2056842B1 - Modified-galactosyl ceramide for the treatment of cancerous diseases - Google Patents

Modified-galactosyl ceramide for the treatment of cancerous diseases Download PDF

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Publication number
EP2056842B1
EP2056842B1 EP07760333A EP07760333A EP2056842B1 EP 2056842 B1 EP2056842 B1 EP 2056842B1 EP 07760333 A EP07760333 A EP 07760333A EP 07760333 A EP07760333 A EP 07760333A EP 2056842 B1 EP2056842 B1 EP 2056842B1
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European Patent Office
Prior art keywords
compound
tumor
use according
cd1d
cells
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German (de)
English (en)
French (fr)
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EP2056842A2 (en
EP2056842A4 (en
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Paul B. Savage
Luc Teyton
Albert Bendelac
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University of Chicago
Brigham Young University
Scripps Research Institute
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University of Chicago
Brigham Young University
Scripps Research Institute
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Priority to PL07760333T priority Critical patent/PL2056842T3/pl
Priority to SI200731114T priority patent/SI2056842T1/sl
Publication of EP2056842A2 publication Critical patent/EP2056842A2/en
Publication of EP2056842A4 publication Critical patent/EP2056842A4/en
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Publication of EP2056842B1 publication Critical patent/EP2056842B1/en
Priority to CY20131100046T priority patent/CY1113545T1/el
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/06—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical being a hydroxyalkyl group esterified by a fatty acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • Natural killer T cells are a population of innate-like memory/effector cells that express both natural killer (NK) receptors and a conserved, semi-invariant T cell receptor (TCR), (V ⁇ 14-J ⁇ 18/V ⁇ 8 in mice and V ⁇ 24-J ⁇ 18/V ⁇ 11 in humans). NKT cells have been implicated in suppression of autoimmunity and graft rejection, promotion of resistance to pathogens, and promotion of tumor immunity.
  • NKT cells recognize foreign and self lipid antigens presented by the CD1 d member of the family of ⁇ 2 microglobulin-associated molecules.
  • a variety of lipids with different structures have been shown to bind CD1d molecules in a unique manner that accommodates a fatty acid chain in each of the two hydrophobic binding pockets (A' and F) of the CD1d molecule.
  • Lipid species capable of binding CD1 d molecules include mycolic acids, diacylglycerols, sphingolipids, polyisoprenoids, lipopeptides, phosphomycoketides and small hydrophobic compounds.
  • the evolutionary conservation of NKT cells is striking, as mouse NKT cells recognize human CD1d plus glycolipid antigen and vice versa.
  • NKT cells respond with vigorous cytokine production within hours of TCR activation by releasing T H1 -type cytokines, including IFN- ⁇ and TNF, as well as T H2 -type cytokines, including IL-4 and IL-13.
  • T H1 -type cytokines including IFN- ⁇ and TNF
  • T H2 -type cytokines including IL-4 and IL-13.
  • NKT cells exhibit a dual junction: they act as immunosuppressive cells via their production of T H2 -type cytokines; and also act as immune promoters to enhance cell-mediated immunity via the production of T H1 -type cytokines.
  • NKT cells have been studied primarily in the context of CD1d presentation of an ⁇ -galactosyl ceramide ( ⁇ GC), termed KRN7000, a glycolipid not considered to be a natural antigen for NKT cells. Isolating and quantifying CD1d responsive NKT cells by flow cytometry has commonly been accomplished using fluorophone-tagged CD1d tetramers loaded with KRN7000. KRN7000 is also used in studies of the influences of NKT cell stimulation on specific disease states. FUJI N. AL., CLINICAL CANCER RESEARCH, vol. 6, no.
  • KRN7000 was reported to stimulate human NKT cells in a CD1-ddependent manner and that immunotherapy using KRN7000 is expected to be useful adjuvant modality in treatment for postoperative residual cancer in humans.
  • supplies of KRN7000 which is derived from a marine sponge, have been limited and this glycolipid has relatively poor solubility in either aqueous or organic solvents.
  • LIU Y ET AL., JOURNAL OF IMMUNOLOGICAL METHODS, vol. 312, no. 1-2, 30, 2006, pages 34-39 discloses that PBS-57 stains mouse and human NKT cells as well as KRN7000 and displays relatively high solubility, and that PBS-57 stimulates NKT cells more effectively than KRN7000.
  • Modified ⁇ -galactosyl ceramides described in the application have been found to stimulate NKT cells more effectively than KRN7000, both in vitro and in vivo. In addition, these molecules may display increased solubility and enhanced loading into CD1d tetramers.
  • the application describes a compound represented by structural formula (I): where R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are defined herein below.
  • the application describes a method of activating an NKT cell comprising contacting the NKT cell with the compound of formula (I) In the presence of a CD1d monomer or tetramer.
  • the application describes a method of stimulating an immune response In a subject.
  • the method includes a step of administering to the subject an effective amount of the compound of formula (I).
  • the method of stimulating an immune response in a subject comprises a step of administering to the subject a population of NKT cells activated by contacting the NKT cells with the compound of formula (I) in the presence of a CD1 molecule.
  • the method of stimulating an immune response in a subject comprises administering to the subject a population of CD1+ antigen presenting cells contacted with the compound of formula (I).
  • the application describes a composition comprising a compound of formula (I) and a physiologically acceptable vehicle.
  • the application describes a method of labeling an NKT cell in a medium comprising steps of complexing a compound of formula (I) with a CD1d tetramer to form a complex, contacting the complex with the NKT cell, removing the unbound complex from the medium, and detecting the complex.
  • the present invention concerns a composition
  • a composition comprising a compound represented by structural formula (II) a tumor-derived antigen, and a physiologically acceptable vehicle, for use in the treatment of cancerous disorders, for stimulating an anti-tumor immune response.
  • the present invention also provides a compound represented by structural formula (II): and a tumor-derived antigen, as a combined preparation for simultaneous, separate or sequential use, for use in the treatment of cancerous disorders.
  • ⁇ GCs modified ⁇ -galactosyl ceramides
  • a prototypical compound of the invention PBS-57 (shown in FIG. 1 ), which includes the above-described modifications, stains mouse and human NKT cells as well as KRN7000 and displays relatively high solubility.
  • PBS-57 shows that it stimulates NKT cells more effectively than KRN7000.
  • glycolipids represented by formula I shown below: wherein:
  • R 5 is (i), X is 13 and Y is 7.
  • R 1 is -CH 3 .
  • R 1 is (i) and R 13 is -CH 3 ;
  • R 5 is (i), and X is 13, and Y is 7;
  • R 6 is -OH;
  • R 7 is -H; and
  • R 8 is C 14 H 29 .
  • glycolipids are defined as follows:
  • glycolipid of the invention designated “PBS-57,” is represented by structural formula II:
  • the compounds described in the application are at least about 10 mg/mL in DMSO under ambient conditions (approximately 20°C). In more suitable embodiments, the compounds described in the application are at least about 20 mg/mL in DMSO at ambient temperature. In further suitable embodiments, the compounds described in the application are at least 80%, at least two-fold, or at least 4-fold relative to the solubility of KRN7000 in DMSO at ambient temperature.
  • compounds described in the application are capable of binding a CD1d monomer ortetramer.
  • the CD1d monomer may be soluble, immobilized on a solid surface, or expressed on the surface of an NKT cell.
  • CD1d tetramers are well known and commercially available.
  • capable of binding a CD1d monomer or tetramer means the ability of the compound to bind CD1d in a lipid binding assay, i.e., a competition assay of a charged glycolipid and an uncharged control and resolution of glycolipid-loaded CD1 molecules by IEF (isoelectric focusing) electrophoresis, as described in Cantu et al., The Paradox of Immune Molecular Recognition of ⁇ -Galactosylceramide: Low Affinity, Low Specificity for CD1d, High Affinity for ⁇ STCRs, Journal of Immunology, 2003, 170:p.673-4682 , the disclosure of which is incorporated herein by reference.
  • binding of the compound to CD1d molecules can be quantified relative to binding of an uncharged glycolipid to CD1d molecules.
  • Compound binding to CD1d can be titrated to saturation and quantified from the IEF gels to determine equilibrium binding constants.
  • a compound will be considered capable of binding a CD1d molecule if it displays a K D less than 1mM when determined using the assay in Cantu et al. cited above.
  • Binding may also be assessed by staining NKT cells with compounds complexed to CD1d tetramers, as described in Liu, Y. et al., J. Immun. Methods 2006, 312: 34-39 .
  • the ability of a compound to bind to the CD1d molecules may be compared to the binding capabilities of KRN7000.
  • the compound exhibits at least 80% of the CD1d binding capability of KRN7000, more preferably at least 90%, more preferably at least two fold, more preferably at least four-fold of the CD1d binding capability of KRN7000.
  • compounds described in the application are capable of activating an NKT cell. Activation of NKT cells can be assessed, e.g., as described in the below and in the examples.
  • Stimulating an NKT cell and “activating an NKT cell” are used interchangeably herein to refer to inducing an observable effect in an NKT cell that is consistent with a cellular response to engagement of the TCR of the NKT cell with an antigen presented in the context of CD1d molecule.
  • Observable effects of activation of NKT cells include secretion of cytokines, clonal proliferation and upregulation of expression of cell surface markers, for example, CD69 molecules, IL-12 receptors and/or CD40L molecules.
  • the NKT cell is contacted with a compound described in the application in the presence of a CD1d monomer or tetramer.
  • a compound as defined in the application stimulates an NKT cell when the compound is complexed with, or bound to, a CD1d monomer or tetramer.
  • Activation of the NKT cell results from contacting the TCR of the NKT cell with the complex, thereby elicting an observable response, such as, e.g., altered cytokine expression.
  • a T cell receptor of an NKT cell refers to the conserved, semi-invariant TCR of NKT cells comprising e.g., V ⁇ 14-J ⁇ 18N/V ⁇ 11 in humans and V ⁇ 14-J ⁇ 18/V ⁇ 8 in mice.
  • contacting an NKT cell refers to the in vitro addition of a compound as described in the application to NKT cells in culture, optionally in the presence of immobilized, soluble, or insoluble CD1d monomers or tetramers or antigen presenting cells (APCs) expressing CD1d molecules, or to the in vivo administration of a compound as defined in the application to a subject.
  • the compound may be presented to the TCR of the NKT cell by CD1d molecules on the surface of an antigen presenting cell (APC), such as a dendritic cell (DC) or macrophage.
  • APC antigen presenting cell
  • CD1d molecules may be plated and the NKT cells and a compound as defined in the application can be added to the CD1d molecules in vitro.
  • cytokines that may be secreted by NKT cells activated as described in the application may include, but are not limited to, IL-10, IL-4, and IL-12, IL-13, GM-CSF, IFN- ⁇ , IL-2, IL-1, IL-6, IL-8, TNF- ⁇ , and TGF-ß. It is appreciated that combinations of any of the above-noted cytokines may be secreted by NKT cells upon activation. Methods for detecting and measuring levels of secreted cytokines are well-known in the art. As will be appreciated, assessing NKT cell activation is suitably accomplished by measuring cytokine expression by the NKT cell relative to a a suitable control.
  • NKT cell proliferation may also be induced by contacting NKT cells with one or more compounds described in the application. Proliferation is suitably measured in vitro by standard methods, e.g. 3 H-thymidine or BrdU incorporation assays.
  • Upregulation of cell surface markers is also suitably observed upon activation of NKT cells.
  • CD69, CD25, CD40L and IL-12 receptors are upregulated upon activation of NKT cells.
  • Immunologic methods such as FACS, may be used to detect upregulation of cell surface markers, as well as other methods commonly employed in the art.
  • Downstream effects of NKT cell activation such as induction of DC maturation, are also observable, e.g., by measuring upregulation of CD80 and/or CD86 on DCs.
  • NKT cells In vivo and ex vivo activation of NKT cells is specifically contemplated in addition to In vitro activation. Presentation of compounds as described in the application to NKT cells in the context of CD1d molecules results in NKT cell activation and dendritic cell maturation. Consequently, these compounds stimulate immune responses against nominal antigens as well as infectious agents and neoplastic malignancies, including solid and hematologic tumors. Both cellular and humoral immunity may be stimulated by administering NKT cell agonist compounds, as further described below.
  • Methods of stimulating an NKT cell in vivo include administering a NKT cell agonist compound to subject.
  • Administration to a subject in accordance with some methods described in the application may include first formulating the NKT cell agonist compound with a physiologically acceptable vehicle and/or excipient to provide desired dosages, stability, etc. Suitable formulations for vaccine preparations and therapeutic compounds are known in the art.
  • Methods of stimulating an NKT cell ex vivo may include use of adoptive transfer methods based on administering cells that have been contacted with NKT cell agonist compounds ex vivo to stimulate NKT cells in a subject.
  • the cells may be NKT cells that are stimulated ex vivo and injected into a subject.
  • the cells may be APCs that have been contacted with compounds described in the application ex vivo to allow loading of the surface-expressed CD1d molecules with the compound for presentation to NKT cells.
  • the ex vivo stimulated NKT cells or loaded APCs can then be administered, e.g., by injection into the subject.
  • Some embodiments described in the application provide a method of stimulating an immune response in a subject.
  • a “subject” is a vertebrate, suitably a mammal, more suitably a human.
  • the subject is suitably an animal model, e.g., a mouse.
  • Stimulating an immune response includes, but is not limited to, inducing a therapeutic or prophylactic effect that is mediated by the immune system of the subject.
  • stimulating an immune response in the context of the application refers to eliciting an NKT cell response in a subject by administering an effective amount of a compound as described in the application the subject, thereby inducing downstream effects such as production of antibodies, antibody heavy chain class switching, maturation of APCs, and stimulation of cytolytic T cells, T helper cells and both T and B memory cells.
  • stimulation of an immune response in a subject may be accomplished by administering to the subject a population of NKT cells that have been activated as described above or a population of CD1d+ antigen presenting cells that have been contacted with a compound as described in the application. Additionally, any combination of the above methods of stimulating an immune response may be suitable.
  • the immune response stimulated as described herein may be an antimicrobial immune response.
  • an immune response suitably promotes clearance of an infectious agent or permits immune control of the agent such that disease symptoms are reduced or resolved, e.g., a persistent or latent infection.
  • the enhanced immune response may be an anticancer or antitumor immune response.
  • an immune response suitably promotes tumor rejection, reduces tumor volume, reduces tumor burden, prevents metastasis, and/or prevents recurrence of the tumor.
  • the tumor may be any solid or hematologic tumor, including but not limited to leukemia, lymphoma, AIDS-related cancers, cancers of the bone, brain, breast, gastrointestinal system, endocrine system, eye, genitourinary tract, germ cells, reproductive organs, head and neck, musculoskeletal system, skin, nervous system or respiratory system.
  • a cancer-specfic immune response may be monitored by several methods, including: 1) measuring cytotoxicity of effector cells, using, e.g., a chromium release assay; 2) measuring cytokine secretion by effector cells; 3) evaluating T cell receptor (TCR) specificities, e.g., by using MHC-peptide multimers; 4) measuring the clonal composition of the T cell response; and/or 5) measuring T cell degranulation.
  • TCR T cell receptor
  • An enhanced immune response is also suitably assessed by the assays such as, e.g. activation of NKT cells, inducing cytokine production, inducing maturation of APCs, enhancing cytolytic and helper T cell functions, enhancing CD8+ and CD4+ T cell recruitment, enhancing antibody production, inducing antibody class switching and breaking tolerance.
  • Stimulating an immune response in a subject as described herein may be accomplished by administering to the subject a composition including a compound as described in the application and in some embodiments, an antigen.
  • the compound and the antigen may or may not induce a detectably enhanced immune response when administered to a subject independently.
  • the compound and the antigen are co-administered to stimulate an immune response in a subject.
  • co-administration is meant to refer to any administration protocol in which a compound as described in the application and an antigen are administered to a subject.
  • the compound and the antigen may be in the same dosage formulations or separate formulations.
  • the compound and antigen are in separate dosage formulations, they can be administered concurrently, simultaneously or sequentially (i.e., administration of one may directly follow administration of the other or they may be given episodically, i.e., one can be given at one time followed by the other at a later time, e.g., within a week), as long as they are given in a manner sufficient to allow both to achieve therapeutically or prophylactically effective amounts in the subject.
  • the compound and the antigen may also be administered by different routes, e.g., one may be administered intravenously while the second is administered intramuscularly, intravenously or orally.
  • the compound is suitably added to a vaccine composition or is co-adminitered with a vaccine composition.
  • Addition of a compound as described in the application to a vaccine composition or co-administration with a vaccine composition may be particularly suitable in cases where the antigen has a low rate of efficacy as a vaccine and/or must be administered in an amount or at a dose greater than what might be considered ideal due to side effects, cost and/or availability of the antigen, etc.
  • examples of such vaccines may include, but are not limited to human papillomavirus vaccines, acute otitis media vaccine (PREVNAR®), influenza vaccines, cholera vaccines and the telomerase cancer vaccine.
  • Administration to a subject may be carried out by any suitable method, including intraperitoneal, intravenous, intramuscular, subcutaneous, transcutaneous, oral, nasopharyngeal or transmucosal absorption, among others.
  • a compound as described in the application is administered in an amount effective to activate an NKT cell or cells such that a prophylactic or therapeutic effect is achieved in the subject, e.g., an antitumor immune response or antimicrobial immune response.
  • Administration to a subject also includes use of adoptive transfer methods based on administering cells that have been contacted with a compound as described in the application ex vivo to stimulate or enhance an immune response in a subject.
  • the cells may be NKT cells that are activated ex vivo and injected into a subject to provide or enhance an immune response to, e.g., cancerous cells or infectious agents.
  • the cells may be APCs that have been contacted with a compound as described in the application ex vivo to allow complexing with the CD1d molecules expressed by the APC.
  • Antigen presenting cells can then be administered, e.g., by injection into the subject, to provide a suitable immune response. This method of administration allows for stimulation of the immune response with minimal exposure of the subject or the subject's cells to the compounds.
  • Administration of compounds as described in the application a subject as described herein appears to exhibit beneficial effects in a dose-dependent manner.
  • administration of larger quantities of the compounds is expected to activate greater numbers of NKT cells or activate NKT cells to a greater degree than does administration of a smaller amount.
  • efficacy is also contemplated at dosages below the level at which toxicity is seen.
  • the specific dosage administered in any given case will be adjusted in accordance with the compound or compounds being administered, the disease to be treated or prevented, the condition of the subject, and other relevant medical factors that may modify the activity of the compound or the response of the subject, as is well known by those skilled in the art.
  • the specific dose for a particular patient depends on age, body weight, general state of health, diet, the timing and mode of administration, the rate of excretion, medicaments used in combination and the severity of the particular disorder to which the therapy is applied.
  • Dosages for a given patient can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the compound of the invention and of a known agent such as aGalCer, such as by means of an appropriate conventional pharmacological or prophylactic protocol.
  • the maximal dosage for a subject is the highest dosage that does not cause undesirable or intolerable side effects.
  • the number of variables in regard to an individual prophylactic or treatment regimen is large, and a considerable range of doses is expected. It is anticipated that dosages of the compound as described herein will prevent or reduce symptoms at least 50% compared to pre-treatment symptoms, it is specifically contemplated that vaccine preparations and compositions as disclosed herein may palliate or alleviate symptoms of the disease without providing a cure, or, in some embodiments, may be used to cure or prevent the disease or disorder.
  • Suitable effective dosage amounts for administering the compounds may be determined by those of skill in the art, but typically range from about 1 microgram to about 10,000 micrograms per kilogram of body weight weekly, although they are typically about 1,000 micrograms or less per kilogram of body weight weekly, In some embodiments, the effective dosage amount ranges from about 10 to about 5,000 micrograms per kilogram of body weight weekly. In another embodiment, the effective dosage amount ranges from about 50 to about 1,000 micrograms per kilogram of body weight weekly. In another embodiment, the effective dosage amount ranges from about 75 to about 500 micrograms per kilogram of body weight weekly.
  • the effective dosage amounts described herein refer to total amounts administered, that is, if more than one compound is administered, the effective dosage amounts correspond to the total amount administered. The compound can be administered as a single weekly dose or as divided doses.
  • a tumor antigen and the compound are co-administered, to a subject to induce an anti-tumor immune response in the subject.
  • co-administration of the antigen with the compound enhances the anti-tumor response and results in inhibition of tumor growth, reduction in tumor burden and treatment of cancer, as described above.
  • compositions with a physiologically acceptable vehicle are suitably included in a composition with a physiologically acceptable vehicle.
  • a “physiologically acceptable” vehicle is any vehicle that is suitable for in vivo administration (e.g., oral, transdermal or parenteral administration) or In vitro use, i.e., cell culture.
  • Suitable physiologically acceptable vehicles for in vivo administration include water, buffered solutions and glucose solutions, among others.
  • a suitable vehicle for cell culture is commercially available cell media.
  • Additional components of the compositions may suitably include excipients such as stabilizers, preservatives, diluents, emulsifiers or lubricants, in addition to the physiologically acceptable vehicle and one or more compounds of the invention.
  • suitable excipients include, but are not limited to, Tween 20, DMSO, sucrose, L-histadine, polysorbate 20 and serum.
  • compositions comprising compounds described herein may be formulated for in vivo use, i.e., therapeutic or prophylactic administration to a subject.
  • the compositions are formulated for parenteral administration.
  • a suitable dosage form for parenteral administration is an injectable.
  • An injectable dosage form may be an isotonic solution or suspension and may be prepared using a suitable dispersion agent, wetting agent or suspension agent, as known in the art.
  • the compositions are formulated for oral administration. Suitable oral dosage forms include tablets, capsules, syrups, troches and wafers, among others.
  • Oral dosage formulations suitably include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, glycols, and others.
  • compositions described herein are not limited to any particular exemplified dosage form, but can be formulated in any manner described in the art, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (2000 ), which is incorporated herein by reference.
  • some embodiments described herein further include CD1d monomers or tetramers.
  • CD1d monomers or tetramers In these compositions, at least a portion of the compound present in the composition is bound to at least a portion of the CD1d monomers or tetramers.
  • amounts of GD1d molecules and concentration of the compound described in the application can be optimized such that substantially all of the CD1d molecules in the composition are bound by compound described in the application.
  • the compound described herein or the compound bound by a CD1d monomer or tetramer) and an antigen are suitably co-formulated in a composition.
  • Antigens included in the composition may be polypeptide or carbohydrate moieties, or combinations thereof, for example, glycoproteins.
  • the antigen may be derived from an infectious agent (e.g., a pathogenic microorganism), a tumor, an endogenous molecule (e.g., a "self" molecule), or, for purposes of study, a nominal antigen, such as ovalbumin.
  • the composition may be also by formulated as a vaccine using a variety of preparative methods known to those of skill in the art. See Remington's Pharmaceutical Sciences, Mack Publishing Co., (2000 ), which is incorporated herein by reference.
  • antigens for inclusion in compositions described in the application are suitably derived from attenuated or killed infectious agents. It will be understood that whole microorganisms or portions thereof (e.g., membrane ghosts; crude membrane preparations, lysates and other preparations of microorganisms) may suitably be included as an antigen. Suitable infectious agents from which an antigen may be derived include, but are not limited to, pathogenic viruses and microorganisms.
  • suitable antigens are obtained or derived from a viral pathogen that is associated with human disease including, but not limited to, HIV/AIDS (Retroviridae, e.g., gp120 molecules for HIV-1 and HIV-2 isolates, HTLV-I, HTLV-11), influenza viruses (Orthomyxoviridae, e.g., types A, B and C), herpes (e.g., herpes simplex viruses, HSV-1 and HSV-2 glycoproteins gB, gD and gH), rotavirus infections (Reoviridae), respiratory infections (parainfluenza and respiratory syncytial viruses), Poliomyelitis "( Picomaviridae, e.g., polioviruses, rhinoviruses), measles and mumps (Paramyxoviridae), Rubella (Togaviridae, e.g., rubella virus), hepatitis (e.g., hepatitis viruses
  • Suitable bacterial and parasitic antigens can also be obtained or derived from known bacterial agents responsible for diseases including, but not limited to, diphtheria, pertussis, tetanus, tuberculosis, bacterial or fungal pneumonia, otitis media, gonorrhea, cholera, typhoid, meningitis, mononucleosis, plague, shigellosis or salmonellosis, Legionnaires' disease, Lyme disease, leprosy, malaria, hookworm, Onchocerciasis, Schistosomiasis, Trypanosomiasis, Leishmaniasis, giardiases, amoebiasis, filariasis, Borrelia, and trichinosis.
  • diseases including, but not limited to, diphtheria, pertussis, tetanus, tuberculosis, bacterial or fungal pneumonia, otitis media, gonorrhea, cholera, typho
  • Still further antigens can be obtained or derived from unconventional pathogens such as the causative agents of kuru, Creutzfeldt-Jakob disease (CJD), scrapie, transmissible mink encephalopathy, and chronic wasting diseases, or from proteinaceous infectious particles such as prions that are associated with mad cow disease.
  • unconventional pathogens such as the causative agents of kuru, Creutzfeldt-Jakob disease (CJD), scrapie, transmissible mink encephalopathy, and chronic wasting diseases
  • proteinaceous infectious particles such as prions that are associated with mad cow disease.
  • pathogens from which antigens can be derived include M. tuberculosis, Chlamydia, N. gonorrhoeae, Shigella, Salmonella, Vibrio cholerae, Treponema pallidum, Pseudomonas, Bordetella pertussis, Brucella, Francisella tularensis, Helicobacter pylori, Leptospira interrogans, Legionella pneumophila, Yersinia pestis, Streptococcus (types A and B), pneumococcus, meningococcus, Haemophilus influenza (type b), Toxoplasma gondii, Moraxella catarrhalis, donovanosis , and actinomycosis; fungal pathogens include candidiasis and aspergillosis; parasitic pathogens include Taenia, flukes, roundworms, amebiasis, giardiasis, Crypto
  • compositions described herein can also be used to provide a suitable immune response against numerous veterinary diseases, such as foot-and-mouth diseases, coronavirus, Pasteurella multocida, Helicobacter, Strongylus vulgaris, Actinobactillus pleuropneumonia, Bovine Viral Diarrhea Virus (BVDV), Klebsiella pneumoniae, E. coli, and Bordetella pertussis, parapertussis and brochiseptica.
  • veterinary diseases such as foot-and-mouth diseases, coronavirus, Pasteurella multocida, Helicobacter, Strongylus vulgaris, Actinobactillus pleuropneumonia, Bovine Viral Diarrhea Virus (BVDV), Klebsiella pneumoniae, E. coli, and Bordetella pertussis, parapertussis and brochiseptica.
  • antigens for inclusion in compositions described herein are suitably tumor-derived antigens or autologous or allogeneic whole tumor cells.
  • the tumor antigen is a tumor specific antigen (TSA) or a tumor associated antigen (TAA).
  • TSA tumor specific antigen
  • TAA tumor associated antigen
  • tumor antigens include cdk4 (melanoma), ⁇ -catenin (melanoma), caspase-8 (squamous cell carcinoma), MAGE-1 and MAGE-3 (melanoma, breast, glioma), tyrosinase (melanoma), surface Ig idiotype (e.g., BCR) (lymphoma), Her-2/neu (breast, ovarian), MUC-1 (breast, pancreatic) and HPV E6 and E7 (cervical carcinoma).
  • cdk4 melanoma
  • ⁇ -catenin melanoma
  • caspase-8 squamous cell carcinoma
  • MAGE-1 and MAGE-3 melanoma, breast, glioma
  • tyrosinase melanoma
  • surface Ig idiotype e.g., BCR
  • Her-2/neu breast, ovarian
  • MUC-1 breast, pancreatic
  • tumor antigens include prostate specific antigen (PSA), sialyl Tn (STn), heat shock proteins and associated tumor peptides (e.g., gp96), ganglioside molecules (e.g., GM2, GD2, and GD3), Carcinoembryonic antigen (CEA) and MART-1.
  • PSA prostate specific antigen
  • STn sialyl Tn
  • ganglioside molecules e.g., GM2, GD2, and GD3
  • CEA Carcinoembryonic antigen
  • MART-1 MART-1.
  • the application discloses a method for labeling NKT cells in a medium.
  • the method can be used to identify NKT cells in a medium from other cell types.
  • a compound as described herein is complexed to soluble CD1d tetramer.
  • the tetramer is suitably labeled.
  • a "label,” as used herein, is any entity that can be assayed. Suitable labels include, but are not limited to strepavidin, biotin and fluorophores, such as, e.g., PE or FITC.
  • the NKT cells are labeled by contact with the labeled compound/CD1d tetramer complex in a suitable medium.
  • a suitable medium may be phosphate buffered saline (PBS) or commercially available cell medium, as known in the art. Unbound glycolipid/tetramer complexes may be removed from media by any means known in the art, e.g. washing and centrifugation of the cells and removal of medium. Cells labeled with the complex may be detected by any suitable means known in the art, such as flow cytometry or fluorescence microscopy.
  • PBS phosphate buffered saline
  • Cells labeled with the complex may be detected by any suitable means known in the art, such as flow cytometry or fluorescence microscopy.
  • PBS-57 was synthesized as shown in FIG. 1 .
  • Reagents corresponding to FIG. 1A are as follows (yields in parentheses): (a) PPh 3 , DPPA, DIAD (79%). (b) AcCl, MeOH (81%). (c) BnBr, NaH, DMF (47%). (d) AcOH, HCl (69% yield). (e) DAST, CH 2 Cl 2 (87%).
  • Reagents corresponding to FIG. 1B are as follows (yields in parentheses): (a) Nervonic acid, DCC, NHS, THF; Ac 2 O, Et 2 N, DMAP, (48%). (b) MeONa, MeOH, (71%).
  • Triacetate 7 (3.4 g, 48.6% yield) was isolated by chromatography (SiO 2 , EtOAc:Hexane 1:8). Sodium metal (230 mg, 10 mmol) was added to MeOH (100 mL). Triacetate 7 (3.4 g, 4.4 mmol) was added, and the mixture was stirred for 1 h then centrifuged (3000 rpm, 5 m) to give a white solid. The supernatant was removed, and the solid rinsed with fresh MeOH (80 mL) to remove any remaining base. After removal of the supernatant, the crude white solid (2.1 g, 71%) was dried under vacuo.
  • the solubility of KRN7000 in DMSO is ⁇ 5 mg/mL while the solubility of PBS-57 in DMSO was 20 mg/mL (22.4 mM).
  • An typical means to isolate and quantify CD1 responsive NKT cells is through flow cytometry using fluorophore tagged CD1d tetramers loaded with sphingoglycolipids.
  • fluorophore tagged CD1d tetramers loaded with sphingoglycolipids.
  • glycolipid-loaded CD1d tetramers were formed. Biotinylated mouse sCD1d molecules (in PBS) were mixed with PBS-57 or KRN7000 at a molar ratio of 1:3 (protein:lipid) and incubated overnight at room temperature. The following day, 80 ⁇ g of streptavidin-PE (Pharmagen) was added to 200 ⁇ g of the CD1-glycolipid mix and incubated at room temperature for 4 hours. Tetramers were stored at 4°C until use.
  • Single cell suspensions of thymocytes and splenocytes were isolated from C57BL/6J mice (Jackson Laboratories, Bar Harbor, Maine) as known in the art.
  • the TCR repertoire of the NKT cells was limited with an invariable V ⁇ subunit (V ⁇ 14 in mice) and varied V ⁇ subunits.
  • 10 6 cells were incubated with 200 ⁇ L staining media (2% BSA, 1% NaN 3 , 10 mM EDTA in PBS) with 2.4G2 (1:100; ATCC, Manassas, VA) and Neutravidin (5 ⁇ g/200 ⁇ l; Molecular Probes, Eugene, OR) for 20 minutes on ice.
  • Example 3 PBS-57 is able to facilitate staining of NKT cells that express a wide variety of V ⁇ TCR subunits.
  • the TCR expressed on NKT cells are limited to a invariant V ⁇ subunit, and a variable V ⁇ subunit that respond to glycolipid presentation by CD1d.
  • V ⁇ subunit a variable V ⁇ subunit that respond to glycolipid presentation by CD1d.
  • NKT hybridomas were established in the Bendelac and Hayakawa laboratories as described previously ( Zhou et al., Lysosomal glycoshingolipid recognition by NKT cells, Science, 2004, 306:p.1786-1788 , and Gui et al., TCR beta chain influences but does not solely control autoreactivity of V alpha 14J281T cells, Journal of Immunology, 2001, 167:p. 6239-6246 ).
  • soluble CD1d (sCD1d) tetramers were loaded with PBS-57 or KRN7000 by the following procedure.
  • Stock reagents of the following were prepared: sCD1d (1 mg/ml in phosphate buffer saline (PBS)); PBS-57 (1 mg/ml in DMSO); Tween 20 (0.5% in PBS); and streptavidin-APC (80 ⁇ g/mL in PBS).
  • 10 ⁇ L sCD1d stock, 1 ⁇ L PBS-57 stock, and 10 ⁇ L Tween 20 stock were mixed, and 79 ⁇ L PBS was added to bring the volume up to 100 ⁇ L. The solution was incubated at 37°C for 3 hours.
  • the mixture was applied to a Microcon YM30 filter (Millipore) that has been previously wetted with PBS (400 ⁇ L).
  • the loaded membrane was centrifuged until only ⁇ 10 ⁇ L of solution remained. The volume was then increased to 100 ⁇ L by addition of PBS.
  • the solution was agitated to aid in freeing the protein from the filter.
  • the Microcon unit was inverted into a fresh Eppendorf tube and the contents were centrifuged into the tube. A 10 ⁇ L aliquot of the solution was removed and the streptavidin-APC solution (5 ⁇ L) was added. The resulting solution was incubated at 37°C for 2 hours.
  • NKT cell hybridomas were suspended in PBS and streptavidin (1 ⁇ g/mL) to block surface biotin of cells for 20 minutes at room temperature. Unloaded sCD1d-streptavidin-cychrome was used to assess the non-specific binding of unloaded empty CD1d tetramers by incubation for 20 minutes at room temperature. Staining of NKT cells was preformed at 37°C for 4 hours using the glycolipid-sCD1d-streptavidin-APC complex. The cells were washed by PBS and assayed via flow cytometry.
  • Example 4 Ability of PBS-57 to facilitate CD1d tetramer staining of NKT cells in human and non-human primate blood samples.
  • mice and human CD1 d tetramers were loaded with PBS-57 as described in Example 2.
  • a majority of the human blood samples contained sufficient NKT cells (>0.08% of CD3-positive cells) to observe staining (14 out of 17 samples), while some samples may have contained too few NKT cells to allow detection of staining (Lee et al., 2002).
  • significant NKT cell staining was observed with a majority of chimpanzee blood samples (6 out of 10 samples) and one quarter of samples from rhesus macaques (12 samples).
  • FIG. 5 Representative dot plots of NKT cell staining in human, chimpanzee and rhesus macaques are shown in FIG. 5 . No staining was seen in samples from pigtail macaques or sooty mangabeys, it may be due to the limited population of NKT cells circulating in the blood and the small sample size.
  • Example 5 Cytokine release in response to PBS-57/CD1d tetramer complex in vitro.
  • Example 6 Cytokine release in response to PBS-57/CD1d tetramer complex in vivo.
  • compositions and methods described herein have been described in terms of exemplary embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved.
  • any numerical value recited herein includes all values from the lower value to the upper value, i.e., all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.

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PL07760333T PL2056842T3 (pl) 2006-04-07 2007-04-09 Modyfikowany galaktozyloceramid do leczenia chorób nowotworowych
SI200731114T SI2056842T1 (sl) 2006-04-07 2007-04-09 Modificiran galaktosil-ceramid za zdravljenje kancerogenih obolenj
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